VPS51-Related Pontocerebellar Hypoplasia-CDG

Mendelian Pathograph 4 Show in embeddings browser Neurodevelopmental Disorder Pontocerebellar Hypoplasia congenital disorder of glycosylation type II

VPS51-related pontocerebellar hypoplasia-CDG is a rare autosomal recessive neurodevelopmental and neurometabolic disorder caused by biallelic VPS51 variants. VPS51 encodes the shared GARP/EARP tethering-complex subunit needed for endosome-derived carrier fusion at the trans-Golgi network and recycling endosomes. Patient cells show reduced assembled GARP/EARP complexes, altered mannose-6-phosphate receptor distribution, lysosomal swelling, and abnormal cellular and serum glycoprotein glycosylation. Reported individuals have severe developmental delay or intellectual disability, microcephaly, epilepsy, hypotonia, thin corpus callosum or pontocerebellar abnormalities, failure to thrive, and variable hepatic, hearing, feeding, and vision involvement.

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1
Inheritance
4
Pathophys.
12
Phenotypes
4
Pathograph
1
Genes
1
Deep Research
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported individuals carry biallelic VPS51 variants, including compound heterozygous and homozygous alleles.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old patient"
The initial report identified compound heterozygous VPS51 variants in an affected child.
PMID:40565173 SUPPORT Human Clinical
"we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met)"
A later sibling report supports biallelic inherited VPS51 disease.
⚙

Pathophysiology

4
VPS51 GARP/EARP tethering-complex deficiency
Biallelic VPS51 variants reduce functional assembly of both GARP and EARP complexes. This impairs tethering/fusion of endosome-derived transport carriers at the trans-Golgi network and recycling endosomes.
VPS51 hgnc:1172
vesicle-mediated transport GO:0016192 ↓ DECREASED retrograde transport, endosome to Golgi GO:0042147 ↓ DECREASED
Golgi apparatus GO:0005794
Downstream
Endosome-Golgi cargo-sorting failure Reduced GARP/EARP assembly alters endosome-derived cargo sorting, including mannose-6-phosphate receptor distribution.
Show evidence (2 references)
PMID:30624672 SUPPORT In Vitro
"Consequently, skin fibroblasts from the patient have reduced levels of fully assembled GARP and EARP complexes."
Patient fibroblasts directly show reduced assembled tethering complexes downstream of VPS51 variants.
PMID:30624672 SUPPORT Other
"At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments."
The report defines the relevant vesicle-fusion role of the VPS51-containing complexes.
Endosome-Golgi cargo-sorting failure
Impaired VPS51-containing tethering disrupts recycling or sorting of endosome-derived cargo to the Golgi and lysosomal system, producing endolysosomal stress in patient cells.
fibroblast CL:0000057
retrograde transport, endosome to Golgi GO:0042147 ↓ DECREASED lysosome organization GO:0007040 ⚠ ABNORMAL
Downstream
Abnormal cellular and serum glycoprotein glycosylation
Show evidence (2 references)
PMID:30624672 SUPPORT In Vitro
"Furthermore, a fraction of the patient's fibroblasts exhibits swelling of lysosomes."
Lysosomal swelling in patient fibroblasts supports downstream endolysosomal dysfunction.
PMID:40565173 SUPPORT In Vitro
"Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism."
Proteomics in VPS51 patient fibroblasts extends the cellular mechanism to vesicular, lysosomal, and metabolic pathway disruption.
Abnormal cellular and serum glycoprotein glycosylation
GARP dysfunction impairs retention and stability of Golgi glycosylation machinery, producing abnormal N-linked and O-linked glycoprotein processing in the VPS51 disease context.
protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL protein O-linked glycosylation GO:0006493 ⚠ ABNORMAL
Show evidence (1 reference)
PMID:34161137 SUPPORT In Vitro
"In summary, we have demonstrated that the GARP-KO human cells have defects in Golgi processing of N- and O-linked oligosaccharides."
GARP loss in human cells produces combined Golgi N- and O-glycan processing defects, matching the VPS51-associated CDG readout.
Neurologic and multisystem dysfunction
The cellular trafficking and glycosylation defects are associated with a severe neurodevelopmental syndrome with pontocerebellar, seizure, feeding, growth, hepatic, sensory, and hypotonia manifestations.
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features."
The initial case report summarizes the multisystem phenotype associated with biallelic VPS51 variants.
PMID:40565173 SUPPORT Human Clinical
"exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia."
The sibling report broadens the reported neurologic and multisystem phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for VPS51-Related Pontocerebellar Hypoplasia-CDG Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Digestive 1
Dysphagia Dysphagia HP:0002015
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists dysphagia.
Ear 1
Hearing impairment Hearing impairment HP:0000365
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists hearing loss.
Head and Neck 2
Microcephaly Microcephaly HP:0000252
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists microcephaly.
Abnormal facial shape Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"lower extremity edema and dysmorphic features."
The cached abstract reports dysmorphic features; HPO maps dysmorphic facial features to abnormal facial shape.
Musculoskeletal 1
Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"microcephaly, hypotonia, epilepsy"
The original report explicitly lists hypotonia.
Nervous System 2
Global developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"severe global developmental delay"
The initial patient was reported with severe global developmental delay.
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"hypotonia, epilepsy, cortical vision impairment"
Epilepsy is included in the original VPS51 disease report.
Growth 1
Failure to thrive Failure to thrive HP:0001508
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"pontocerebellar abnormalities, failure to thrive, liver dysfunction"
The initial case report explicitly includes failure to thrive.
Other 4
Thin corpus callosum Thin corpus callosum HP:0033725
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"developmental delay, a thin corpus callosum, severe intellectual disability"
The sibling report explicitly includes thin corpus callosum.
Cerebral visual impairment Cerebral visual impairment HP:0100704
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"epilepsy, cortical vision impairment, pontocerebellar abnormalities"
Cortical vision impairment is represented by the HPO cerebral visual impairment term.
Abnormality of the liver Abnormality of the liver HP:0001392
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"failure to thrive, liver dysfunction, lower extremity edema"
Liver dysfunction is captured with the generic HPO liver abnormality term because the cached abstract does not specify a narrower hepatic feature.
Pedal edema Pedal edema HP:0010741
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"liver dysfunction, lower extremity edema and dysmorphic features."
Lower-extremity edema maps to the HPO pedal edema term.
🧬

Genetic Associations

1
VPS51 biallelic pathogenic variants (Loss of function mutation)
Gene: VPS51 hgnc:1172 relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome."
This supports a pathogenic VPS51 allele with severe protein instability.
PMID:30624672 SUPPORT In Vitro
"the other mutant allele produces a protein with a single amino acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits."
This supports impaired tethering-complex assembly as the effect of the second VPS51 allele.
{ }

Source YAML

click to show 
name: VPS51-Related Pontocerebellar Hypoplasia-CDG
creation_date: "2026-07-06T12:00:00Z"
category: Mendelian
description: >-
  VPS51-related pontocerebellar hypoplasia-CDG is a rare autosomal recessive
  neurodevelopmental and neurometabolic disorder caused by biallelic VPS51
  variants. VPS51 encodes the shared GARP/EARP tethering-complex subunit needed
  for endosome-derived carrier fusion at the trans-Golgi network and recycling
  endosomes. Patient cells show reduced assembled GARP/EARP complexes, altered
  mannose-6-phosphate receptor distribution, lysosomal swelling, and abnormal
  cellular and serum glycoprotein glycosylation. Reported individuals have
  severe developmental delay or intellectual disability, microcephaly, epilepsy,
  hypotonia, thin corpus callosum or pontocerebellar abnormalities, failure to
  thrive, and variable hepatic, hearing, feeding, and vision involvement.
parents:
- Neurodevelopmental Disorder
- Pontocerebellar Hypoplasia
- congenital disorder of glycosylation type II
synonyms:
- VPS51-related neurodevelopmental disorder
- VPS51 deficiency
- VPS51-related GARP/EARP complex dysfunction
- pontocerebellar hypoplasia-CDG due to VPS51 deficiency
notes: >-
  WP-068 seed OMIM:618606 is retained as an external assertion. No exact local
  MONDO class was found for VPS51-related pontocerebellar hypoplasia-CDG, so
  disease_term is intentionally omitted pending ontology coverage. The local
  PCH1A candidate was audited and not used because PCH1A is a VRK1/anterior-horn
  cell disorder, whereas VPS51 disease is a GARP/EARP vesicular-trafficking and
  Golgi-glycosylation disorder.
external_assertions:
- name: OMIM VPS51-related pontocerebellar hypoplasia-CDG record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618606
  description: >-
    OMIM phenotype identifier supplied by WP-068 for VPS51-related
    pontocerebellar hypoplasia-CDG.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      WP-068 classification 19.6.67.01: Complex Molecule and Organelle
      Metabolism, disorders of organelle biogenesis, dynamics and interactions,
      disorders of vesicular trafficking.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported individuals carry biallelic VPS51 variants, including compound
    heterozygous and homozygous alleles.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By exome sequencing, we have identified compound heterozygous mutations in
      the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old
      patient
    explanation: >-
      The initial report identified compound heterozygous VPS51 variants in an
      affected child.
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we present two siblings with a novel homozygous variant in VPS51 (Vacuolar
      protein sorting 51) gene (c.1511C>T; p.Thr504Met)
    explanation: >-
      A later sibling report supports biallelic inherited VPS51 disease.
pathophysiology:
- name: VPS51 GARP/EARP tethering-complex deficiency
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    Biallelic VPS51 variants reduce functional assembly of both GARP and EARP
    complexes. This impairs tethering/fusion of endosome-derived transport
    carriers at the trans-Golgi network and recycling endosomes.
  genes:
  - preferred_term: VPS51
    term:
      id: hgnc:1172
      label: VPS51
  biological_processes:
  - preferred_term: vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0016192
      label: vesicle-mediated transport
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consequently, skin fibroblasts from the patient have reduced levels of
      fully assembled GARP and EARP complexes.
    explanation: >-
      Patient fibroblasts directly show reduced assembled tethering complexes
      downstream of VPS51 variants.
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At these locations, GARP and EARP function to promote the fusion of
      endosome-derived transport carriers with their corresponding compartments.
    explanation: >-
      The report defines the relevant vesicle-fusion role of the VPS51-containing
      complexes.
  downstream:
  - target: Endosome-Golgi cargo-sorting failure
    causal_link_type: DIRECT
    description: >-
      Reduced GARP/EARP assembly alters endosome-derived cargo sorting, including
      mannose-6-phosphate receptor distribution.
    evidence:
    - reference: PMID:30624672
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the patient's fibroblasts display altered distribution of the
        cation-independent mannose 6-phosphate receptor, which normally sorts
        acid hydrolases to lysosomes.
      explanation: >-
        Patient fibroblast imaging directly supports altered cargo receptor
        distribution.
- name: Endosome-Golgi cargo-sorting failure
  description: >-
    Impaired VPS51-containing tethering disrupts recycling or sorting of
    endosome-derived cargo to the Golgi and lysosomal system, producing
    endolysosomal stress in patient cells.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  - preferred_term: lysosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007040
      label: lysosome organization
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, a fraction of the patient's fibroblasts exhibits swelling of
      lysosomes.
    explanation: >-
      Lysosomal swelling in patient fibroblasts supports downstream
      endolysosomal dysfunction.
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Proteomic profiling revealed 585 differentially expressed proteins,
      indicating disruptions in vesicular trafficking, lysosomal function, and
      mitochondrial metabolism.
    explanation: >-
      Proteomics in VPS51 patient fibroblasts extends the cellular mechanism to
      vesicular, lysosomal, and metabolic pathway disruption.
  downstream:
  - target: Abnormal cellular and serum glycoprotein glycosylation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired GARP-dependent maintenance of Golgi glycosylation enzymes
    evidence:
    - reference: PMID:34161137
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        a patient with a neurodevelopmental disorder caused by mutations in the
        VPS51 subunit of GARP and EARP was shown to exhibit abnormal
        glycosylation of cellular and serum glycoproteins
      explanation: >-
        The GARP glycosylation study explicitly connects VPS51 disease to
        abnormal cellular and serum glycoprotein glycosylation.
- name: Abnormal cellular and serum glycoprotein glycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    GARP dysfunction impairs retention and stability of Golgi glycosylation
    machinery, producing abnormal N-linked and O-linked glycoprotein processing
    in the VPS51 disease context.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  - preferred_term: O-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59521
      label: O-glycan
  evidence:
  - reference: PMID:34161137
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In summary, we have demonstrated that the GARP-KO human cells have defects
      in Golgi processing of N- and O-linked oligosaccharides.
    explanation: >-
      GARP loss in human cells produces combined Golgi N- and O-glycan
      processing defects, matching the VPS51-associated CDG readout.
- name: Neurologic and multisystem dysfunction
  description: >-
    The cellular trafficking and glycosylation defects are associated with a
    severe neurodevelopmental syndrome with pontocerebellar, seizure, feeding,
    growth, hepatic, sensory, and hypotonia manifestations.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe global developmental delay, microcephaly, hypotonia, epilepsy,
      cortical vision impairment, pontocerebellar abnormalities, failure to
      thrive, liver dysfunction, lower extremity edema and dysmorphic features.
    explanation: >-
      The initial case report summarizes the multisystem phenotype associated
      with biallelic VPS51 variants.
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exhibiting developmental delay, a thin corpus callosum, severe
      intellectual disability, epilepsy, microcephaly, hearing loss, and
      dysphagia.
    explanation: >-
      The sibling report broadens the reported neurologic and multisystem
      phenotype.
phenotypes:
- category: Neurological
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Severe developmental delay is a core reported feature.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe global developmental delay"
    explanation: >-
      The initial patient was reported with severe global developmental delay.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: >-
    Microcephaly is reported in the original patient and later affected
    siblings.
  evidence:
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, a thin corpus callosum, severe intellectual
      disability, epilepsy, microcephaly, hearing loss, and dysphagia.
    explanation: >-
      The sibling report explicitly lists microcephaly.
- category: Neurological
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Epilepsy is reported in VPS51-related disease.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia, epilepsy, cortical vision impairment"
    explanation: >-
      Epilepsy is included in the original VPS51 disease report.
- category: Neurological
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Hypotonia is part of the original presentation.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hypotonia, epilepsy"
    explanation: >-
      The original report explicitly lists hypotonia.
- category: Neurological
  name: Thin corpus callosum
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  description: >-
    Thin corpus callosum was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, a thin corpus callosum, severe intellectual disability"
    explanation: >-
      The sibling report explicitly includes thin corpus callosum.
- category: Growth
  name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  description: >-
    Failure to thrive is reported in the original case.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pontocerebellar abnormalities, failure to thrive, liver dysfunction"
    explanation: >-
      The initial case report explicitly includes failure to thrive.
- category: Neurological
  name: Cerebral visual impairment
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  description: >-
    Cortical visual impairment was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy, cortical vision impairment, pontocerebellar abnormalities"
    explanation: >-
      Cortical vision impairment is represented by the HPO cerebral visual
      impairment term.
- category: Hepatic
  name: Abnormality of the liver
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  description: >-
    Liver dysfunction was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, liver dysfunction, lower extremity edema"
    explanation: >-
      Liver dysfunction is captured with the generic HPO liver abnormality term
      because the cached abstract does not specify a narrower hepatic feature.
- category: Fluid regulation
  name: Pedal edema
  phenotype_term:
    preferred_term: Pedal edema
    term:
      id: HP:0010741
      label: Pedal edema
  description: >-
    Lower-extremity edema was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver dysfunction, lower extremity edema and dysmorphic features."
    explanation: >-
      Lower-extremity edema maps to the HPO pedal edema term.
- category: Craniofacial
  name: Abnormal facial shape
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: >-
    Dysmorphic features were reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lower extremity edema and dysmorphic features."
    explanation: >-
      The cached abstract reports dysmorphic features; HPO maps dysmorphic
      facial features to abnormal facial shape.
- category: Hearing
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  description: >-
    Hearing loss was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hearing loss, and dysphagia."
    explanation: >-
      The sibling report explicitly lists hearing loss.
- category: Feeding
  name: Dysphagia
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  description: >-
    Dysphagia was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hearing loss, and dysphagia."
    explanation: >-
      The sibling report explicitly lists dysphagia.
genetic:
- name: VPS51 biallelic pathogenic variants
  association: Loss of function mutation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: VPS51
    term:
      id: hgnc:1172
      label: VPS51
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    Reported pathogenic alleles include compound heterozygous variants with an
    unstable frameshift product and a missense protein that assembles less
    efficiently into GARP/EARP, and a homozygous p.Thr504Met sibling variant.
  evidence:
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation in one allele causes a frameshift that produces a longer but
      highly unstable protein that is degraded by the proteasome.
    explanation: >-
      This supports a pathogenic VPS51 allele with severe protein instability.
  - reference: PMID:30624672
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the other mutant allele produces a protein with a single amino acid
      substitution that is stable but assembles less efficiently with the other
      GARP/EARP subunits.
    explanation: >-
      This supports impaired tethering-complex assembly as the effect of the
      second VPS51 allele.
📚

References & Deep Research

Deep Research

1
VPS51-Related Pontocerebellar Hypoplasia-CDG Deep Research Fallback ▸

VPS51-Related Pontocerebellar Hypoplasia-CDG Deep Research Fallback

Scope

No provider-generated deep research artifact was present on the WP-068 branch. This fallback audit documents the literature scope used to curate and review the VPS51-related entry from cached PubMed references.

Evidence Scope Used For Curation

  • PMID:30624672 for the original biallelic VPS51 case, reduced assembled GARP/EARP complexes, mannose-6-phosphate receptor redistribution, lysosomal swelling, and the clinical phenotype including developmental delay, microcephaly, hypotonia, epilepsy, cortical visual impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema, and dysmorphic features.
  • PMID:40565173 for later affected siblings with a homozygous VPS51 variant, fibroblast proteomics showing vesicular, lysosomal, and mitochondrial pathway disruption, and additional phenotypes including thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia.
  • PMID:34161137 for the mechanistic link between GARP disruption and abnormal cellular and serum glycoprotein glycosylation.

Curation Conclusions

The supported model is biallelic VPS51 dysfunction causing combined GARP/EARP tethering-complex deficiency. Patient-cell evidence supports impaired endosome-derived cargo sorting, lysosomal abnormalities, and downstream Golgi glycoprotein processing defects. The curated phenotype set should include the core neurologic and growth features plus sensory, hepatic, edema, dysmorphic, hearing, and swallowing features reported in the cached literature.